POS1442 AMELIORATION OF IGA VASCULITIS BY SUPPRESSION OF THE PATHOLOGICAL EXPANSION OF TFH17 CELLS
Authors: X. MA, Q. Jiang, Y. Shan, X. Chi, H. Jiang
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Immunoglobulin A vasculitis (IgAV), also named Henoch–Schönlein purpura, is a systemic vasculitis characterized by the deposition of IgA1-dominant immune complexes in small vessels that often involves the skin, joints, gastrointestinal tract, and kidney [1-3]. Research indicated increased frequencies of circulating activated B cells and plasmablasts in IgAV, which may serve as the source of the rising IgA levels [4]. T follicular helper (Tfh) 17 cells are considered to support the activation of B cells and help germinal center (GC) B cells switch to high-affinity IgA production. In human, Tfh17 cells prompt naive B cells to produce higher concentrations of IgA [5]. T cell-deficient mice that receive an adoptive transfer of Th17-Tfh cells show induced development of IgA-expressing GC B cells and an increase in the concentration of IgA. Transfer of non-Tfh17 phenotype CD4<sup>+</sup> T cells leads to higher amounts of IgG in serum but fails to increase the serum IgA level [6]. Therefore, targeted therapy against Tfh17 cells may specifically inhibit the secretion of IgA and thereby ameliorate IgAV condition. <h3>Objectives</h3> Our previous study has confirmed that Tfh17 cells increase in the peripheral blood of IgAV patients [7]. However, there is no further study on the pathogenesis of IgAV. To evaluate the pathological role of Tfh17 cells in IgAV, we investigated the mechanism responsible for the differentiation of Tfh17 and the production of IgA in IgAV patients and IgAV rats respectively, and explored how to ameliorate IgAV by modulating Tfh17 generation. <h3>Methods</h3> Peripheral blood mononuclear cells from IgAV patients were analyzed by flow cytometry. In vitro culture was performed to assess the modulation of cytokine-induced phenotypes. IgAV rat model was established by intragastric administration of mixed solution, intraperitoneal injection of ovalbumin and Freund's adjuvant. IgAV rats were used to explore the therapeutic effects of IL-6 blockade and the regulatory functions of IL-6 and TGF-β-producing dendritic cells in Tfh17 cells. Serum cytokine and IgA levels were measured by ELISA while histopathological changes were evaluated by H&amp;E and PAS staining. Flow cytometry and immunofluorescence staining were used to detect T cell and GC B cell phenotypes in circulation and tissues of IgAV rats. <h3>Results</h3> Frequency of CD4<sup>+</sup>CXCR5<sup>+</sup>CCR6<sup>+</sup> Tfh17 cells were increased in IgAV patients and associated with disease severity. IL-6 promoted the dendritic cell production of TGF-β and Tfh17 differentiation. Blockade of IL-6 signaling using tocilizumab inhibited Tfh17 differentiation, resulting in reduction of the germinal center and IgA production. Suppression of Tfh17 cells using IL-6 blockade greatly ameliorated clinical symptoms such as hemorrhagic rash and bloody stool and decreased IgA deposition and mesangial proliferation in the kidney in IgAV rats. <h3>Conclusion</h3> Our findings suggest that suppression of Tfh17 differentiation can alleviate IgA-mediated vasculitis and may permit the development of tailored medicines for treating IgAV. <h3>References</h3> [1]Davin JC, Coppo R. Henoch-Schönlein Purpura Nephritis in Children. Nat Rev Nephrol. 2014, 10 (10): 563-573. [2]Pillebout E, Sunderkötter C. IgA vasculitis. Semin Immunopathol. 2021, 43 (5): 729-738. [3]Thervet E, Pillebout E, Guillevin L, <i>et al</i>. Outcome after childhood Henoch-Schönlein purpura. Lancet. 2003, 361 (9351): 81. [4]Kawakami T, Watabe H, Mizoguchi M, <i>et al</i>. Elevated serum IgA anticardiolipin antibody levels in adult Henoch-Schönlein Purpura. Br J Dermatol. 2006, 155 (5): 983-987. [5]Morita R, Schmitt N, Bentebibel SE, <i>et al</i>. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011, 34 (1): 108-121. [6]Hirota K, Turner JE, Villa M, <i>et al.</i> Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol. 2013, 14 (4): 372-379. [7]Ma X, Nakayamada S, Wang J. Multi-Source Pathways of T Follicular Helper Cell Differentiation. Front Immunol. 2021, 12: 621105. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.